Fatty acid synthase (FAS) is an enzyme required to convert carbohydrates to fatty acids. In normal humans, the fatty acid synthetic pathway is down-regulated because of sufficiently high levels of dietary fat. However, in a wide variety of human malignancies and their precursor lesions, such as, prostate cancer, ovarian cancer, and breast cancer, the tissues express high levels of fatty acid synthase resulting in high levels of fatty acids. An up-regulation of FAS in most human cancers leads to the notion that FAS plays a role in the development, maintenance, and/or enhancement of the malignant cancer phenotype and that FAS can be a target for anticancer drug development.
About 1.2 billion people in the world are overweight and at least 300 million of them are obese. In the United States, more than 97 million adults—that's more than half—are overweight and almost one in five adults is obese. Reduction of the fatty acid synthesis in the obese can be an effective treatment for obesity.
Treatment of cancer cells in vitro with cerulenin, a covalent inactivator of the β-ketoacyl synthase reaction on FAS, led to cell death by means of apoptosis, demonstrating that cancer cells with highly active fatty acid synthesis require a functional pathway (Pizer et al. (1996) Cancer Res. 56, 2745-2747). Cerulenin, however, has limited in vivo activity. FAS has been shown to be one of the genes regulated by Her-2/neu at the level of transcription, translation, and biosynthetic activity (Menedez et al. (2005) Drug New Perspect, 18(6), July/August). This Her-2/neu-induced up-regulation of breast-cancer associated FAS is inhibitable by anti-Her-2/neu antibodies such as trastuzumab. Studies with C75, an inhibitor of fatty acid synthesis, have shown anti-tumor activity with inhibition of fatty acid synthesis in tumor tissue (Kuhajda et al. (2000) Proc. Natl. Acad. Sci. vol. 97, no. 7, 3450-3454). FAS inhibitors have also been shown to activate weight-reducing pathways (Loftus, T. M. et al. (2000)Science 288, 2379-2381).
As fatty acid synthesis plays a role in cancer and weight gain pathways, there continues to be a need to develop effective fatty acid synthesis inhibitors.